Ophthalmic solution of difluprednate

Abstract

The present invention provides a method of treatment of inflammatory disorder of the eye, said method comprising administering into the eye of a person in need thereof, an aqueous solution comprising difluprednate as the sole active ingredient at a concentration of 0.02% to 0.04% weight by volume in an aqueous vehicle, wherein the solution is free of oil and wherein the solution is administered twice-a-day. The present invention also provides an ophthalmic solution comprising a. therapeutically effective concentration of difluprednate, a crystal growth inhibitor and pharmaceutically acceptable amounts of a solubilizer comprising a mixture of i. quaternary ammonium compound and ii. polyethoxylated castor oil, b. in an aqueous vehicle. wherein the crystal growth inhibitor is polyvinyl alcohol or its derivatives.

The invention claimed is: 
     
       1. A clear ophthalmic aqueous solution comprising:
 (a) about 0.02% w/v to about 0.45% w/v difluprednate; 
 (b) about 0.1% w/v to about 5.0% w/v crystal growth inhibitor; 
 (c) about 0.002% w/v to about 0.08% w/v quaternary ammonium compound; and 
 (d) about 1.5% w/v to about 6.0% w/v polyethoxylated castor oil; 
 wherein osmolality of the solution is about 250 to about 375 mOsm/kg. 
 
     
     
       2. The clear ophthalmic aqueous solution of  claim 1 , wherein the difluprednate is not in particulate form. 
     
     
       3. The clear ophthalmic aqueous solution of  claim 1 , wherein the crystal growth inhibitor is polyvinyl alcohol or a derivative thereof. 
     
     
       4. The clear ophthalmic aqueous solution of  claim 1 , wherein the quaternary ammonium compound is benzalkonium chloride. 
     
     
       5. The clear ophthalmic aqueous solution of  claim 1 , wherein the osmolality of the solution is about 270 to about 350 mOsm/kg. 
     
     
       6. The clear ophthalmic aqueous solution of  claim 1 , further comprising a preservative, a chelating agent, a pH adjusting agent, a cosolvent, a viscosity increasing agent, or a combination thereof. 
     
     
       7. The clear ophthalmic aqueous solution of  claim 6 , wherein the preservative comprises biguanide, boric acid, N-lauroyl sarcosine, sodium salt of N-lauroyl sarcosine, or combination thereof. 
     
     
       8. The clear ophthalmic aqueous solution of  claim 7 , comprising about 0.002% w/v to about 0.02% w/v polyhexamethylene biguanide, about 0.05% w/v to 1.5% w/v boric acid, about 0.01% w/v to 0.1% w/v N-lauroyl sarcosine, or combination thereof. 
     
     
       9. The clear ophthalmic aqueous solution of  claim 6 , wherein the chelating agent comprises edetate disodium, ethylenediamine tetracetic acid, edetic acid, disodium edetate dihydrate, diethylenetriamine pentaacetic acid, or combination thereof. 
     
     
       10. The clear ophthalmic aqueous solution of  claim 6 , comprising about 0.01% w/v to 0.1% w/v of the chelating agent. 
     
     
       11. The clear ophthalmic aqueous solution of  claim 6 , wherein the pH adjusting agent comprises acetic acid, sodium acetate, tartaric acid, sodium tartrate, citric acid, sodium citrate, hydrochloric acid, sodium hydroxide, or combination thereof. 
     
     
       12. The clear ophthalmic aqueous solution of  claim 6 , wherein the cosolvent comprises glycerol, propylene glycol, ethylene glycol, polyethylene glycol, glycofurol, or combination thereof. 
     
     
       13. The clear ophthalmic aqueous solution of  claim 12 , comprising about 1.0% w/v to about 3.0% w/v glycerol. 
     
     
       14. The clear ophthalmic aqueous solution of  claim 1 , wherein percent transmission of the solution is greater than 90% at 650 nm. 
     
     
       15. The clear ophthalmic aqueous solution of  claim 1 , wherein pH of the solution is about 5.0 to about 6.0. 
     
     
       16. The clear ophthalmic aqueous solution of  claim 1 , comprising (a) about 0.02% to about 0.04% w/v difluprednate, (b) about 0.5% w/v to about 3.0% w/v of the crystal growth inhibitor; (c) about 0.01% w/v to about 0.05% w/v of the quaternary ammonium compound; and (d) about 3.0% w/v to about 5.0% w/v of the polyethoxylated castor oil. 
     
     
       17. A method of treating an inflammatory disorder of the eye, comprising administering the clear ophthalmic aqueous solution of  claim 6  into the eye of a person in need thereof. 
     
     
       18. The method of  claim 17 , wherein the administering is twice daily. 
     
     
       19. The method of  claim 17 , wherein the inflammatory disorder of the eye is pain and inflammation associated with ocular surgery and/or uveitis, wherein the uveitis is acute anterior uveitis, endogenous anterior uveitis, chronic uveitis, or a combination thereof. 
     
     
       20. The method of  claim 17 , wherein the inflammatory disorder of the eye is acute anterior uveitis or chronic uveitis.